PROVIDED. The overall goals of this project are to determine the changes in the brain that occur in early frontotemporal dementia (FTD)and to use amyotropic lateral sclerosis (ALS)as a model for understanding the earliest manifestation of FTD. Four groups of subjects (20/group) will be studied on a 4 Tesla Bruker/Siemens MRI scanner: (1) patients with early FTD (CDR 0.5),(2) ALS patients with mild personality or executive function impairment, (3) patients with MCI or early AD and (4) cognitively normal age-matched controls. The'following measurements will be obtained: 1) Atrophy patterns in cerebral cortex, using tensor based morphometry, and subcortical structures, including hippocampal subfields, detected with high resolution MRI. 2) Cerebral blood flow in gray matter (GM) and white matter (WM) quantified with arterial spin-labeled perfusion MRI. 3) Integrity of WM tracts thought to be involved in FTD, ALS, and early AD, as measured by fractional anisotrophy (FA)from diffusion tensor imaging (DTI). We will also assess progressive neurodegeneration in FTD and ALS relative to patients with MCI or early AD using longitudinal MRI, perfusion, and DTI measurements. These goals Will be accomplished by testing the following hypotheses: 1) ALS and early FTD show GM loss and reduced perfusion in the frontal insular and anterior cingulate cortex compared to controls. There will be reduced FA for the following WM tracts: uncinate, thalamic-frontal, striatal frontal, anterior callosm, superior longitudinal fasciculus and cingulum. The posterior callosum and Meyer's loop will serve as control tracts because they are not expected to change with these diseases. 2) ALS and FTD involve the frontal insular and anterior cingulate cortex compared to amnestic MCI/early AD, who will show greater hippocampal atrophy, especially in posterior hippocampus, and reduced FA in posterior cingulum and posterior callosal tracts. Differential effects between ALS and FTD versus MCI/early AD will be explored in hippocampal subfield thickness. 3) Rates of change in FTD and ALS involving frontal insular and anterior cingulate cortex is greater than that compared to 20 amnestic MCI/early AD and 20 controls. MCI/early AD show greater hippocampal atrophy and reduced FA in cingulum than FTD/ALS longitudinally. 4) We will further explore our preliminary findings of greater medial temporal lobe atrophy in ubiquitin-positive than tau-positive patients, and greater general cortical thinning, caudate atrophy, and WM lesions in tau-positive than ubiquitin-positive patients. The results of this project will provide new information concerning brain changes that occur in early FTD, and will help distinguish early FTD from early AD. These results should be directly applicable to future clinical trials and diagnosis of subjects with cognitive impairments.